3-Substituted phenylalkyl amines

ABSTRACT

Novel 3-phenoxyphenylalkyl amines and the amides, alcohols, tetrazoles, and carbamates related thereto as well as novel intermediates useful in the preparation of such compounds. The compounds of this invention are useful as anti-inflammatory, analgesic, and antipyretic agents.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part of my application Ser. No.828,756, filed May 28, 1969, and now U.S. Pat. No. 3,600,437 whichapplication is a continuation-in-part of my prior applications Ser. No.823,477, filed May 9, 1969 and Ser. No. 752,801, filed Aug. 15, 1968both now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to novel 3-phenoxyphenyl alkylamines, theirpharmaceutically acceptable acid addition salts, and the correspondingamides, alcohols, tetrazoles, and carbamates having anti-inflammatoryactivity and mild, aspirin-like, analgesic and anti-pyretic activity.

A number of humans and animals are known to suffer from variousrheumatic conditions involving inflammation, swelling, tenderness,decreased mobility, pain, and fever. While there are a number ofpresently available anti-inflammatory agents which have been found to beeffective in the symptomatic treatment of conditions such as rheumatoidarthritis, rheumatoid spondylitis, degenerative joint disease(osteoarthritis) of the hip, such agents have a number of undesirableside effects. One of the most frequently occurring side effects of thepresently accepted nonsteroidal anti-inflammatory agents is gastricirritation, ulceration, and exacerbation of existing ulcers. Thus, thesearch for improved anti-inflammatory agents continues.

The present invention provides novel compounds which are excellentanti-inflammatory agents, and which, in addition to theiranti-inflammatory activity, exhibit mild, aspirin-like analgesic andanti-pyretic activity. Since they are not acidic in nature, they areexpected to be free of the gastro-intestinal irritating and ulceratingeffects found in most non-steroidal anti-inflammatory agents.

SUMMARY

This invention relates to novel 2-(3-phenoxyphenyl)-alkylamines, theirpharmaceutically acceptable acid addition salts, and the amides,alcohols, tetrazoles, and carbamates related thereto, to novelpharmaceutical compositions useful in the treatment of inflammation,pain, and fever in humans and animals, and to intermediates useful inthe preparation of such compounds. Some of the compounds of thisinvention also enhance the analgesic activity of a number of analgesicagents.

It is a primary object of this invention to provide novel3-phenoxyphenyl alkylamines and the amides, alcohols, tetrazoles, andcarbamates related thereto.

Still a further object is to provide therapeutic compositions for therelief of inflammation, and the accompanying pain, swelling, fever, andthe like in man and animals.

A further object is to provide methods for treating inflammation in manand animals.

Further objects will become apparent to those skilled in the art fromthe following description and claims.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The novel 3-phenoxyphenyl alkylamines, their pharmaceutically acceptableacid addition salts and the corresponding amides, alcohols, carbamates,and tetrazoles of this invention are represented by general formula I:##SPC1##

wherein

R₁ is hydrogen, C₁ -C₅ alkyl, C₂ -C₅ alkenyl, or C₂ -C₅ alkynyl;

n is an integer from 0 to 3; and

Z is ##STR1## wherein each R₂ is the same or different and is hydrogen,hydroxy, C₁ -C₅ alkyl, or --CH₂ --COOR₃ ; where R₃ is hydrogen, C₁ to C₅alkyl, or a pharmaceutically acceptable cation,

(b) --CH₂ OR₄, R₄ being hydrogen, acetyl, propionyl, carbamyl,N-methylcarbamyl, or N,N-dimethylcarbamyl; ##STR2## , or (d) when n =1-3, ##STR3## wherein each R₅ is the same or different, and is hydrogen,C₁ -C₅ alkyl, C₂ -C₆ alkenyl, cyclopropyl, or cyclopropylmethyl, allyl,3-methyl-2-butenyl, or phenethyl;

and the pharmaceutically acceptable acid addition salts thereof.

The term "acid addition salts" refers to salts prepared by reacting thefree amine with an organic or inorganic acid. Representative saltsinclude the hydrochloride, hydrobromide, sulfate, bisulfate, acetate,valerate, oleate, laurate, borate, benzoate, lactate, phosphate,tosylate, citrate, maleate, fumarate succinate, tartrate, napsylate(salt of 2-naphthalenesulfonic acid) and the like.

"C₁ -C₅ alkyl" refers to both straight and branched chain alkylsincluding methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,tert-butyl, iso-butyl, n-amyl, iso-amyl, neo-pentyl, and the like.

"C₂ -C₅ alkenyl" refers to the C₂ -C₅ alkyl groups, as defined above,from which a hydrogen atom has been removed from each of two adjacentcarbon atoms to produce ethylenic unsaturation; e.g., vinyl, allyl,methallyl, 1-pentenyl, and the like.

"C₁ -C₅ alkynyl" refers to the C₂ -C₅ alkyl groups as defined above,from which two hydrogen atoms have been removed from each of twoadjacent carbon atoms to produce acetylenic unsaturation; e.g., ethynyl,propargyl, 2-butynyl, 1-pentynyl, and the like.

Compounds represented by general formula I are excellentanti-inflammatory agents, many of them having an ED₅₀ of from 1-10mg./kg. in the erythema blocking assay. All of the compounds of thisinvention are useful in the treatment of inflammatory diseases inmammals. In addition to their anti-inflammatory activity, the compoundsexhibit mild analgesic and anti-pyretic activity. Therapeuticcompositions comprising, as their active ingredient(s), one or morecompounds of general formula I in association with a pharmaceuticallyacceptable diluent or carrier, are also provided by this invention. Thecompounds are generally administered to mammals in dosages of from0.5-50 mg./kg. of body weight daily, either in single or divided dosesover a period of 24 hours.

It is to be understood that both the d and l isomers of the α-alkylcompounds of this invention are contemplated within the scope of theinvention. Thus, for example, the α-alkylamine can be resolved intotheir d and l isomers by methods well known in the art.

Some of the compounds of this invention, particularly those wherein n is1, R₁ is methyl, and Z is --NH₂ or a salt thereof, have surprisinglybeen found to enhance the level of analgesia obtained with certainanalgesic agents such as the esters of d-1,2-diphenyl-2-hydroxy-3-methyl4(substituted amino)butanes, particularly α-d-propoxyphene (identifiedchemically asα-d-1,2-diphenyl-2-propionoxy-3-methyl-4-dimethylaminobutane) whenco-administered therewith.

Enhancement of analgesia is effected when about one part by weight of acompound of this invention is administered substantially simultaneously,that is, co-administrated, or administered from 1 hour before to 1 hourafter the administration of from 0.005 to 20 parts by weight of theanalgesic agent. Generally speaking, in order to obtain a greater levelof analgesia, from 0.5 to 50 mg./kg. of a compound of this invention isadministered with the usual therapeutic dosage of the analgesic agent.

Representative compounds of the present invention include the following:

2-(3-Phenoxyphenyl)propanol

2-(3-Phenoxyphenyl)propionamide

2-(3-Phenoxyphenyl)ethylcarbamate

N-methyl-2-(3-phenoxyphenyl)propionamide

N-methyl-2-(3-phenoxyphenyl)propylcarbamate

N,n-dimethyl-2-(3-phenoxyphenyl)propionamide

N,n-dimethyl-2-(3-phenoxyphenyl)-n-pentyl carbamate

N-cyclopropylmethyl-2-(3-phenoxyphenyl)propionamide

2-(3-Phenoxyphenyl)ethylamine

N-cyclopropyl-2-(3-phenoxyphenyl)butylamine maleate

2-(3-Phenoxyphenyl)propionohydroxamic acid

N-cyclopropylmethyl-2-(3-phenoxyphenyl)propylamine hydrochloride

N-methyl-2-(3-phenoxyphenyl)propylamine sulfate

N,n-dimethyl-2-(3-phenoxyphenyl)propylamine hydrochloride

2-(3-Phenoxyphenyl)propylamine hydrochloride

2-(3-Phenoxyphenyl)butylamine sulfate

3-(3-Phenoxyphenyl)butanol

3-(3-Phenoxyphenyl)butyl acetate

2-(3-Phenoxyphenyl)propyl propionate

5-(α-Methyl-3-phenoxybenzyl)-1H-tetrazole

5-(3-phenoxyphenyl)-1H-tetrazole

4-(3-Phenoxyphenyl)valeramide

The compounds of this invention can be prepared by methods which arewell known for the preparation of arylalkylamines, arylalkanoic acidamides, arylalkanols and derivatives thereof. While various routes canbe employed in obtaining the compounds of this invention, a number ofthe preferred reaction sequences are represented and describedhereinbelow. In the following representations and discussion, R₁ -R₄ areas defined in formula I, and "Ar" represents the ##SPC2##

moiety of formula I.

A. Acids ##STR4##

The methyl group of m-phenoxytoluene is halogenated by the action ofN-bromosuccinimide, N-chlorosuccinimide, sulfurylchloride, or likehalogenating agent, with a suitable catalyst, such as benzoyl peroxideor azo-bis-iso-butyronitrile, in an inert solvent such as carbontetrachloride, or other halogenated hydrocarbon. The resultinghalomethyl diphenyl ether is caused to react with sodium or potassiumcyanide, advantageously in dimethyl sulfoxide solution. The nitrile thusobtained is hydrolyzed to the corresponding carboxylic acid by theaction of either acidic or basic reagents by methods well known in theart. ##STR5##

The nitrile prepared in the above illustration can be alkylated with analiphatic halide or tosylate (R₁ X) in liquid ammonia in the presence ofsodium amide to provide an α-aliphatic substituted nitrile. Thealkylated nitrile is hydrolyzed as above to yield the correspondingcarboxylic acid (Sequence IIa). In a similar fashion, an arylacetic acidor arylacetamide may be alkylated α- to the carboxyl group, asillustrated in reaction sequence IIb-IIc. In the case of thearylacetamide, the resulting α-alkyl derivative can be hydrolyzed to thecorresponding carboxylic acid if desired.

In another method, as illustrated in sequences IId and IIe, anarylacetate ester, such as the ethyl ester, or an arylacetonitrile canbe converted to the corresponding malonic ester or cyanoacetic ester bythe action of metallic sodium and diethyl carbonate. Either of thesederivatives may then be alkylated. Such alkylation is usually effectedby reacting the malonic ester or cyanoacetic ester with a strongly basicreagent, such as sodium ethoxide, sodium methoxide, potassiumtert-butoxide, sodium hydride, and the like, thereby forming a carbanionon the α-carbon atom. Subsequent treatment of the carbanion intermediatewith an alkylating agent, such as an alkyl halide or tosylate (R₁ X)yields the corresponding α-alkyl malonic ester or cyanoacetic esterderivative. Either of these may be hydrolyzed to the correspondingα-alkylaryl malonic acid which is then decarboxylated by methods wellknown in the art, thus yielding the desired α-alkyl arylacetic acid.

A nitrile prepared according to reaction sequence I can optionally bemethylated according to the following procedure (Sequence III): Thenitrile is condensed with ethyl formate under basic conditions, forexample, in the presence of sodium hydride or sodium methoxide in aninert hydrocarbon solvent such as in benzene. The resultinghydroxymethylene derivative is benzoylated by the action of eitherbenzoic anhydride or benzoyl chloride and pyridine; and the benzoicester is then hydrogenated in the presence of a noble metal catalyst toyield the desired α-methylarylacetonitrile, which is then hydrolyzed asabove.

The desired α-methylarylacetonitrile can optionally be prepared by thefollowing series of reactions (Sequence IV); the m-phenoxyacetophenone(prepared by the method of an Ullman Ether synthesis) is reduced eitherwith hydrogen in the presence of a noble metal catalyst or with a metalhydride, such as lithium aluminum hydride, lithium or sodiumborohydride, or the like, to the corresponding carbinol. Conversion ofthis carbinol to the corresponding bromide can be accomplished bytreating the carbinol with phosphorus tribromide, preferably in an inertsolvent such as chloroform, benzene, carbon tetrachloride, and the like.The bromide thus obtained is then reacted with sodium cyanideadvantageously in a dimethyl sulfoxide solution to yield a nitrile whichis hydrolyzed, as set forth above, to the desired carboxylic acid.

An alternate method of synthesizing α-alkyl -(m-phenoxyphenyl)aceticacids involves the use of the Arndt-Eistert reaction, as illustrated insequence V, using m-phenoxy benzoic acid as the starting material.

The phenoxyphenyl alkanoic acids can also be prepared by the Willgerodtreaction (Sequence VI). In this reaction, a m-phenoxyphenyl alkyl ketoneis heated with, for example, morpholine and sulfur, and the resultingthioamide hydrolyzed to yield the desired alkanoic acid derivative whichcan be alkylated by treatment with two equivalents of sodium amide inliquid ammonia, followed by the addition of the alkyl halide or tosylate(R₁ X) as illustrated in sequence IIb.

The acid intermediates in which n is other than O can be prepared bywell-known methods with the well-known Wittig reaction as illustrated inreaction schemes VIIa and VIIb. The intermediate unsaturated esters (asin VIIa) or nitriles (as in VIIb) can be hydrogenated in the presence ofa noble metal catalyst, such as platinum, and the resulting saturatedesters and nitriles can be hydrolyzed, as set forth above, to thedesired carboxylic acids.

C. Esters ##STR6##

The carboxylic acid intermediates prepared by methods described in theabove reaction sequences are converted to the corresponding esters bywell-known methods of the prior art such as by heating the acid with analcohol in the presence of a mineral acid (VIIIa), or by converting theacid to the corresponding acid chloride, followed by reacting said acidchloride with an alcohol, preferably in the presence of an HCl scavenger(VIIIb).

D. Amides ##STR7##

The amides of this invention are obtained by the reaction of theaforementioned acid chloride with an amine. This reaction is customarilycarried out in an inert solvent such as chloroform, benzene, or carbontetrachloride, in the presence of an acid scavenger such as pyridine, K₂CO₃, and the like, or in a tertiary amine solvent such as collidine,lutidine, triethylamine, and the like.

E. Alcohols ##STR8##

The esters whose preparation is outlined above can be reduced with ametal hydride such as, for example, lithium aluminum hydride, to thecorresponding alcohol by the methods of the prior art.

F. Esters ##STR9##

The new alcohols obtained as set forth in reaction sequence X can beconverted to ester derivatives by well-known methods, such as, forexample, treatment of the alcohol with an acid chloride or acidanhydride, preferably in the presence of a tertiary amine such aspyridine or triethylamine. Such a reaction using acetic anhydride, forexample, yields the desired acetate ester.

G. Carbamates ##STR10##

Carbamate derivatives of the alcohols obtained as in reaction sequence Xcan also be prepared, either by reaction of the alcohol with aniso-cyanate or by reaction of the alcohol with a carbamoyl halide, suchas N,N-dimethylcarbamoyl chloride. These reactions are preferablyconducted using a tertiary amine solvent, such as pyridine ortriethylamine.

H. Amines ##STR11##

The amine derivatives of this invention can be prepared by well-knownprocedures, such as, for example, reduction of an amide with a metalhydride reagent such as lithium aluminum hydride (Sequence XIIa). Inthose cases where primary amines are desired, these can conveniently beprepared by hydrogenation of the corresponding nitriles in the presenceof ammonia and an active catalyst, such as Raney nickel (Sequence XIIb).

A suitably substituted aryl alkyl ketone may optionally be condensedwith nitromethane and the resulting nitro-styrene derivative can then bereduced either catalytically or with a metal hydride reagent such aslithium aluminum hydride, to yield the desired amine (Reaction SequenceXIIc).

I. Hydroxamic Acids ##STR12##

The esters prepared according to reaction sequence VIIIa and VIIIb canbe converted into hydroxamic acids by treatment with hydroxylamine bywell-known procedures.

J. Tetrazoles ##STR13##

Nitriles which are prepared by the methods of sequences I, IIa, III, orIV, or by other well-known methods, can be converted to thecorresponding tetrazoles by treating them with, for example, sodiumazide, using dimethylformamide as the reaction solvent (in the mannerdescribed by Finnigan, W. G., Henry, R. A., and Lofquist, R., J. Am.Chem. Soc., 80, 2908 (1958)). de

The following examples further illustrate the present invention.

EXAMPLE 1 A. Preparation of 2-(3-phenoxyphenyl)acetic acid

To 26 ml. of morpholine were added 42.4 g. of m-phenoxyacetophenone and9.6 g. of sulfur. The reaction mixture was refluxed with stirring for 20hours. To the reaction mixture was then added 700 ml. of 15 percentaqueous potassium hydroxide and a small amount of ethyl alcohol. Thereaction mixture was refluxed with stirring for an additional 20 hours.About 200 ml. of the solvent was distilled out. The remaining reactionmixture was filtered while hot, partially cooled with ice, and acidifiedwith concentrated hydrochloric acid, whereupon an oily precipitateformed and then crystallized. The crystalline precipitate was filtered,washed several times with water, and dried to yield 45.9 g. of crudeproduct as a yellow-orange solid. The crude product was suspended inboiling hexane, and ethyl acetate was added until the product went intosolution. The solution was then treated with carbon, filtered andcooled, to yield 22.7 g. of white flakes of 2-(3-phenoxyphenyl)aceticacid, m.p., 84°-86°C.; pK'a = 6.9.

Analysis, Calc. for C₁₄ H₁₂ O₃ : C, 73.66; H, 5.30. Found: C, 73.85; H,5.35.

B. Methyl 2-(3-phenoxyphenyl)acetate

2-(3-Phenoxyphenyl)acetic acid is dissolved in chloroform, stirred, andthionyl chloride in chloroform is added slowly. The reaction mixture isrefluxed gently with stirring for about 3 hours, and then evaporated todryness to yield the corresponding acid chloride. The acid chloride istaken up in chloroform and the resulting solution added dropwise withstirring to an excess of cold methyl alcohol. The reaction mixture iscooled to below 10°C., and then allowed to warm to room temperature. Thesolvent is stripped off on a rotary evaporator and the residue distilledto yield methyl 2-(3-phenoxyphenyl)acetate. This compound can be used asan intermediate in the preparation of the new alcohol compounds of thisinvention.

EXAMPLE 2 Preparation of 2-(3-Phenoxyphenyl)propionic acid

A. 3-phenoxyacetophenone.

A mixture consisting of 908 g. (6.68 moles) of m-hydroxyacetophenone,4500 g. (28.6 moles) of bromobenzene, 996 g. (7.2 moles) of anhydrouspotassium carbonate, and 300 g. of copper bronze was heated under refluxwith stirring until water evolution was complete, using a Dean-Starkwater separator. The mixture was then stirred and refluxed for 24 hours.After cooling to room temperature, the reaction was diluted with anequal volume of CHCl₃ and filtered. The filtrate was washed with 5percent HCl, then with 5 percent NaOH, with water, dried over Na₂ SO₄,and evaporated in vacuo. The residual oil was distilled through a 15 cm.Vigreux column, yielding 918 g. of 3-phenoxyacetophenone, b.p.,120°-121°C. (0.09 mm.), n_(D) ²⁵ = 1.5868.

Analysis, Calc. for C₁₄ H₁₂ O₂ : C, 79.22; H, 5.70. Found: C, 79.39; H,5.79.

B. α-methyl-3-phenoxybenzyl alcohol

A stirred solution of 700 g. of m-phenoxyacetophenone in 3000 ml.anhydrous methanol was cooled to 0° in an ice-acetone bath. Sodiumborohydride, 136 g. (3.6 moles) was added to this solution in smallportions at such a rate that the temperature never rose above 10°C.After borohydride addition was complete, the reaction mixture wasallowed to warm to room temperature and stirred for 18 hours. It wasthen stirred and refluxed for 8 hours. About 400 ml. of methanol wasdistilled out and the remaining solution was evaporated to aboutone-third its original volume in vacuo and poured into ice water. Thismixture was extracted twice with ether, acidified with 6NHCl, and againextracted with ether. The ether extracts were combined, washed withsaturated NaCl solution, dried over anhydrous sodium sulfate, andevaporated in vacuo. The residual oil was distilled through a 15 cm.Vigreux column, yielding 666 g. of α-methyl-3-phenoxybenzyl alcohol,b.p., 132°-134°C. (0.35 mm.). n_(D) ²⁵ = 1.5809.

Analysis, Calc. for C₁₄ H₁₄ O₂ : C, 78.48; H, 6.59. Found: C, 78.75; H,6.31.

C. α-methyl-3-phenoxybenzyl bromide.

A stirred solution of 1357 g. of α-methyl-3-phenoxybenzyl alcohol in5000 ml. anhydrous CCl₄ (predried over molecular sieve) was cooled to0°C. To this was added 1760 g. PBr₃, stirring and cooling beingmaintained at such a rate that the temperature remained at 0°-5°C.during the addition. The reaction mixture was then allowed to warm toroom temperature and was stirred at room temperature overnight (ca. 12hours). The reaction mixture was then poured into ice water and theorganic phase separated. The aqueous phase was extracted with CCl₄ andthe combined extracts were washed three times with water, dried overanhydrous sodium sulfate, and evaporated to dryness in vacuo to yield1702 g. of α-methyl-3-phenoxybenzyl bromide as a heavy viscous oil,n_(D) ²⁵ = 1.5993;

Analysis, Calc. for C₁₄ H₁₃ BrO: C, 60.44; H, 4.71; Br, 28.73. Found: C,60.62; H, 4.89; Br, 28.47.

D. 2-(3-phenoxyphenyl)propionitrile

A well-stirred suspension of 316 g. of 98 percent sodium cyanide in 5000ml. of anhydrous dimethyl sulfoxide (previously dried over molecularsieve) was warmed to 55°-60°C. and maintained at this temperature while1702 g. of α-methyl-3-phenoxybenzyl bromide was slowly added. After thebromide addition was completed, the temperature was raised to 75°C., andthe mixture stirred at this temperature for 1.5 hours. The mixture wasthen allowed to cool to room temperature, and was stirred overnight atroom temperature and then poured into ice water. The resulting aqueoussuspension was extracted twice with ethyl acetate, and then with ether.The organic extract was washed twice with a sodium chloride solution,once with water, and dried over anhydrous sodium sulfate. Evaporation ofthe solvent in vacuo left an oily residue which was distilled through a15 cm. Vigreux column to yield 1136 g. of2-(3-phenoxyphenyl)propionitrile, b.p., 141°-148°C. (0.1 mm.), n_(D) ²⁵= 1.5678.

Analysis, Calc. for C₁₅ H₁₃ NO: C, 80.69; H, 5.87; N, 6.27. Found: C,80.89; H, 6.10; N, 6.14.

E. 2-(3-phenoxyphenyl)propionic Acid

A mixture of 223 g. of 2-(3-phenoxyphenyl)propionitrile and 400 g. ofsodium hydroxide in 1600 ml. of 50 percent ethanol was refluxed withstirring for 72 hours. After cooling to room temperature, the reactionmixture was poured into ice water. The resulting solution was washedwith ether, acidified with concentrated HCl, and extracted with ether.The ether extract was washed with water, dried over anhydrous sodiumsulfate, and evaporated to dryness in vacuo. The residual oil wasdistilled to yield 203.5 g. (84 percent) of 2-(3-phenoxyphenyl)propionicacid as a viscous oil; b.p., 168°-171°C. (0.11 mm.), n_(D) ²⁵ = 1.5742,pK'a = 7.3.

Analysis, Calc. for C₁₅ H₁₄ O₃ : C, 74.36; H, 5.83. Found: C, 74.48; H,6.05.

EXAMPLE 3 5-(α-Methyl-3-phenoxybenzyl)-1H-tetrazole

A well-stirred mixture of 10 g. of 2-(3-phenoxyphenyl)propionitrile,prepared according to the method of example 2D, 3.9 g. of sodium azide,3.2 g. of ammonium chloride, a few milligrams of lithium chloride and200 ml. of dry dimethylformamide was heated to 125°C. for about 18hours. Afer cooling, the dimethylformamide was partially evaporated invacuo and the remaining reaction mixture was poured into water. Afteradjusting this aqueous mixture to pH4 with dilute HCl, the productprecipitated as an oil. After the aqueous solution was removed bydecantation, the oil solidified. It was recrystallized from a mixture ofethyl acetate and n-hexane to yield 4.7 g. of5-(α-methyl-3-phenoxybenzyl)-1H-tetrazole, m.p., 92°-95°C., pK'a 5.8.

Analysis, Calc. for C₁₅ H₁₄ N₄ O: C, 67.65; H, 5.30; N, 21.04. Found: C,67.41; H, 5.33; N, 21.05.

EXAMPLE 4 2-(3-Phenoxyphenyl)propionamide

A solution of 0.5 M of 2-(3-phenoxyphenyl)propionyl chloride in 300 ml.of dry ethyl ether was added dropwise to 2 liters of liquid ammonia withstirring. After addition was complete, the reaction was stirred for onehour, and 500 ml. of diethyl ether were added. The reaction was stirredovernight, whereby the excess ammonia was evaporated. Dilutehydrochloric acid was added to the reaction. The ether layer wasseparated, washed with sodium hydroxide, water, and dried over sodiumsulfate. Evaporation of the ether in vacuo left a gummy residue whichcrystallized after trituration with cold hexane. Recrystallization fromethyl acetate and hexane yielded 76.2 g. of2-(3-phenoxyphenyl)propionamide, m.p., 67°-69°C.

Analysis, Calc. for C₁₅ H₁₅ NO₂ : C, 74.66; H, 6.27; N, 5.81. Found: C,74.01; H, 6.30; N, 6.15.

EXAMPLE 5 N,N-Dimethyl-2-(3-phenoxyphenyl)propionamide

To 400 ml. of dry chloroform were added 72.6 g. of2-(3-phenoxyphenyl)propionic acid prepared according to the method ofExample 2E, and 36.9 g. of thionyl chloride. The reaction mixture wasrefluxed with stirring for about 3 hours. The chloroform was thenevaporated and the residue azeotroped twice with benzene. The residuewas dissolved in ethyl ether and added, with stirring and cooling, to asolution of 45 g. of dimethylamine in ethyl ether. The temperature wasmaintained at approximately 0°C. or below during the addition. Thereaction mixture was allowed to warm to room temperature, refluxedgently for 1.5 hours, poured into ice and water, acidified, and theethyl ether layer separated. The aqueous layer was extracted with ethylether. The ether extracts were combined, washed with water, dried oversodium sulfate and evaporated to white solid. The solid was dissolved inboiling hexane and allowed to cool slowly to room temperature to yield67.6 g. of N,N-dimethyl-2-(3-phenoxyphenyl)propionamide, m.p.,73.5°-76°C.,

Analysis, Calc. for C₁₇ H₁₉ NO₂ : C, 75.80; H, 7.11; N, 5.20. Found: C,75.93; H, 6.90; N, 5.27.

EXAMPLE 6 N-Cyclopropylmethyl-2-(3-phenoxyphenyl)pripionamide

To 350 ml. of chloroform were added 60.5 g. of2-(3-phenoxyphenyl)propionic acid and 30.4 g. of thionyl chloride. Thereaction mixture was refluxed with stirring overnight, evaporated, andthe residue azeotroped three times with benzene. The resulting oily acidchloride was taken up in chloroform. Forty grams ofaminomethylcyclopropane hydrochloride were dissolved in a small amountof water, made basic with 5N sodium hydroxide, and extracted withchloroform. The aqueous layer was saturated with sodium chloride andagain extracted with chloroform. The chloroform extracts were combinedand dried over sodium carbonate and sodium sulfate. The extracts werefiltered, and 50 ml. of triethylamine added thereto. The mixture wascooled in an ice-acetone bath. To this was added dropwise the chloroformsolution of the acid chloride. Cooling and stirring were maintainedduring the addition.

The reaction mixture was allowed to warm to room temperature, stirredfor 30 minutes, warmed to the reflux point, allowed to cool to roomtemperature, and stirred overnight. The solution was then partiallyevaporated and poured into an ice-water mixture. The chloroform layerwas washed with dilute hydrochloric acid, dried over sodium sulfate, andevaporated to an oily residue. The residue was covered with hexane andscratched, whereupon a crystalline solid formed. The crystalline solidwas taken up in boiling ethyl acetate, and hexane was added toturbidity. The solution was allowed to cool to yield 50.6 g. ofcrystalline N-cyclopropylmethyl-2-(3-phenoxyphenyl)propionamide, m.p.,94.5°-96°C.

Analysis, Calc. for C₁₉ H₂₁ NO₂ : C, 77.26; H, 7.17; N, 4.74. Found: C,77.14; H, 7.17; N, 4.71.

EXAMPLES 7-17

The following compounds were prepared according to the method of Example6, using appropriate starting materials.

N-Methyl-2-(3-phenoxyphenyl)butyramide, m.p., 84°-86°C.

Analysis, Calc. for C₁₇ H₁₉ NO₂ : C, 75.81; H, 7.11; N, 5.20. Found: C,75.60; H, 7.11; N, 5.00.

N-Methyl-2-(3-phenoxyphenyl)propionamide, m.p., 57°-58°C.

Analysis, Calc. for C₁₆ H₁₇ NO₂ : C, 75.27; H, 6.71; N, 5.49. Found: C,75.51; H, 6.86; N, 5.61.

N-Cyclopropyl-2-(3-phenoxyphenyl)propionamide, m.p., 65°-67°C.

Analysis, Calc. for C₁₈ H₁₉ NO₂ : C, 76.84; H, 6.81; N, 4.98. Found: C,77.06; H, 6.99; N, 4.94.

N-Methyl-(3-phenoxyphenyl)acetamide, m.p., 64°-68°C., which gave asatisfactory Nmr spectrum and which was used without purification.

N,N-Dimethyl-3-phenoxyphenylacetamide, an oil which have a satisfactoryNmr spectrum and which was used without purification.

Ethyl-[N-cyclopropyl-N-(2-[3-phenoxyphenyl]propyl)]carbamate, which gavea satisfactory Nmr spectrum and which was used without purification.

N-Methyl-N-(2-[3-phenoxyphenyl]propyl)cyclopropane carboxamide, whichgave a satisfactory Nmr spectrum.

Analysis, Calc. for C₂₀ H₂₅ NO₂ : C, 77.64; H, 7.49; N, 4.53; O, 10.34.Found: C, 77.90; H, 7.71; N, 4.40; O, 10.58.

Ethyl-N-(2-phenethyl)-N-[2-(3-phenoxyphenyl)propyl]carbamate, which gavea satisfactory Nmr spectrum.

Analysis, Calc. for C₂₆ H₂₉ NO₃ : C, 77.39; H, 7.24; N, 3.47; O, 11.90.Found: C, 77.17; H, 7.46; N, 3.65; O, 12.04.

N-Allyl-2-(3-phenoxyphenyl)propionamide, which gave a satisfactory Nmrspectrum.

Analysis, Calc. for C₁₈ H₁₉ NO₂ : C, 76.84; H, 6.81; N, 4.98. Found: C,76.85; H, 7.03; N, 4.93.

N-2-(phenyl)ethyl-2-(3-phenoxyphenyl)propionamide, m.p., 55°-56°C.;which gave a satisfactory Nmr spectrum and which was used withoutfurther purification.

3-(3-Phenoxyphenyl)butyramide, m.p., 50°-53°C.

Analysis, Calc. for C₁₆ H₁₇ NO₂ : C, 75.27; H, 6.71; N, 5.49. Found: C,75.51; H, 6.71; N, 5.27.

EXAMPLE 18 N,N-Dimethyl-2-(3-phenoxyphenyl)propylamine hydrochloride

To a flame dried flask were added, under nitrogen, 6.08 g. of lithiumaluminum hydride and 500 ml. of ethyl ether. The mixture was stirred atroom temperature for approximately 30 minutes. To the mixture was addeddropwise 67.3 g. of N,N-dimethyl-2-(3-phenoxyphenyl)propionamide(prepared according to the method of Example 5) dissolved in 800 ml. ofethyl ether. The reaction mixture was refluxed with stirring overnight.To the reaction mixture was then added 4.65 ml. of water, 3.5 ml. of 20percent sodium hydroxide, and 16.5 ml. of water. The reaction mixturewas then poured onto ice, additional sodium hydroxide was added, and thereaction was extracted with ethyl ether. The ether layer was washed withwater and extracted with dilute hydrochloric acid. The acid extract wasthen washed with ethyl ether, basified with sodium hydroxide, andextracted twice with ethyl ether. The ether extracts were washed withwater, dried over sodium sulfate, and evaporated to an oil. The oil wasdistilled to yield 39.2 g. ofN,N-dimethyl-2-(3-phenoxyphenyl)propylamine, b.p., 114°-120°C./0.1 mm.,m.w. 255.

Analysis, Calc for C₁₇ H₂₁ NO: C, 79.96; H, 8.29; N, 5.49. Found: C,79.76; H, 8.06; N, 5.38.

Thirty-four grams of the above amine were dissolved in approximately 800ml. of dry ethyl ether, and hydrogen chloride gas was passed into thesolution until saturated. The resulting white solid precipitate wasfiltered, washed with ethyl ether, partially dried, and recrystallizedfrom boiling ethyl alcohol to yield 34.3 g. ofN,N-dimethyl-2-(3-phenoxyphenyl)propylamine hydrochloride, m.p.,215°-217°C.

Analysis, Calc. for C₁₇ H₂₁ NO.HCl: C, 69.96; H, 7.60; N, 4.80. Found:C, 69.68; H, 7.40; N, 4.90.

EXAMPLES 19-31

The following compounds were prepared according to the method of Example18, from the corresponding amide using appropriate starting materials.

N-Methyl-2-(3-phenoxyphenyl)butylamine hydrochloride, m.p., 124°-126°C.

Analysis, Calc. for C₁₇ H₂₁ NO.HCl: C, 69.96; H, 7.60; N, 4.80. Found:C, 69.83; H, 7.80; N, 4.87.

N-Methyl-2-(3-phenoxyphenyl)propylamine hydrochloride, m.p., 160°-162°C.

Analysis, Calc. for C₁₆ H₁₉ NO.HCl: C, 69.17; H, 7.25; N, 5.04. Found:C, 69.21; H, 7.02; N, 5.30.

N-Cyclopropylmethyl-2-(3-phenoxyphenyl)propylamine hydrochloride,m.p.,115°-117°C.

Analysis, Calc. for C₁₉ H₂₃ NO.HCl: C, 71.79; H, 7.61; N, 4.40. Found:C, 71.96; H, 7.46; N, 4.39.

N-Cyclopropyl-2-(3-phenoxyphenyl)propylamine hydrochloride, m.p.,129°-131°C., pK'a 7.9.

Analysis, Calc. for C₁₈ H₂₁ NO.HCl: C, 71.15; H, 7.30; N, 4.61. Found:C, 71.23; H, 7.48; N, 4.61.

N-Methyl-2-(3-phenoxyphenyl)ethylamine hydrochloride, m.p., 139°-141°C.,pK'a 9.7.

Analysis, Calc. for C₁₅ H₁₇ NO.HCl: C, 68.30; H, 6.88; N, 5.31. Found:C, 68.21; H, 6.75; N, 5.13.

N,N-Dimethyl-2-(3-phenoxyphenyl)ethylamine hydrochloride, m.p.,163°-165°C., pK'a 8.5.

Analysis, Calc. for C₁₆ H₁₉ NO.HCl: C, 69.18; H, 7.26; N, 5.04; O, 5.76.Found: C, 69.38; H, 7.45; N, 5.07; O, 5.59.

N-Methyl-N-cyclopropyl-2-(3-phenoxyphenyl)propylamine hydrochloride,m.p., 129°-130°C., pK'a 6.9.

Analysis, Calc. for C₁₉ H₂₃ NO.HCl: C, 71.80; H, 7.61; N, 4.41. Found:C, 71.53; H, 7.84; N, 4.58.

N-Methyl-N-cyclopropylmethyl-2-(3-phenoxyphenyl)propylaminehydrochloride, m.p., 90°-92°C, pK'a 8.3.

Analysis, Calc. for C₂₀ H₂₅ NO.HCl: C, 72.38; H, 7.90; N, 4.22; O, 4.82.Found: C, 72.33; H, 7.90; N, 4.41; O, 5.09.

N-Methyl-N-(2-phenylethyl)-2-(3-phenoxyphenyl)propylamine hydrochloride,m.p., 137°-138°C, pK'a 7.7.

Analysis, Calc. for C₂₄ H₂₇ NO.HCl: C, 75.46; H, 7.39; N, 3.67. Found:C, 75.23; H, 7.58; N, 3.56.

N-Allyl-2-(3-phenoxyphenyl)propylamine hydrochloride, m.p., 118°-120°C.,pK'a 8.5.

Analysis, Calc. for C₁₈ H₂₁ NO: C, 71.16; H, 7.30; N, 4.61. Found: C,71.13; H, 7.50; N, 4.54.

N-(2-Phenylethyl)-2-(3-phenoxyphenyl)propylamine hydrochloride, m.p.120°-124°C.

Analysis, Calc. for C₂₃ H₂₅ NO.HCl: C, 75.08; H, 7.12; N, 3.81. Found:C, 75.11; H, 7.30; N, 3.64.

N-Methyl-3-(3-phenoxyphenyl)butylamine hydrochloride, m.p., 124°-126°C.,pK'a 10.0.

Analysis, Calc. for C₁₇ H₂₁ NO.HCl: C, 69.96; H, 7.60; N, 4.80. Found:C, 69.83; H, 7.80; N, 4.87.

3-(3-Phenoxyphenyl)butylamine hydrochloride, m.p., 133°-135°C., pK'a10.0.

Analysis, Calc. for C₁₆ H₁₉ NO.HCl: C, 69.17; H, 7.26; N, 5.04. Found:C, 69.36; H, 7.47; N, 5.06.

EXAMPLE 32N-Methyl-N-(3-methylbut-2-enyl)-2-(3-phenoxyphenyl)propylaminehydrochloride

A mixture of 23.9 g. of N-Methyl-2-(3-phenoxyphenyl)propylamine,prepared according to the method of Example 20, and 13.8 g. of potassiumcarbonate in benzene was treated with 20.8 g. of1-chloro-3-methyl-2-butene. The reaction mixture was refluxed withmechanical stirring for about 60 hours. After cooling to roomtemperature, the reaction was washed with water and extracted withdilute hydrochloric acid. The acidic extract was basified with sodiumhydroxide solution and extracted with ether. The ether extract waswashed twice with water and dried over sodium sulfate. Dry hydrogenchloride gas was passed into the ethereal solution and the resultingprecipitated hydrochloride salt was filtered and recrystallized from analcohol-ether mixture to yield 11.5 g. of the titled product, m.p.120°-122°C., pK'a 8.5.

Analysis, Calc. for C₂₁ H₂₇ NO.HCl: C, 72.92; H, 8.16; N, 4.05. Found:C, 72.87; H, 8.34; N, 4.04

EXAMPLE 33

N-Methyl-N-allyl-2-(3-phenoxyphenyl)propylamine hydrochloride, m.p.135°-136°C., pK'a 7.6, was prepared generally by the method of Example18.

Analysis, Calc. for C₁₉ H₂₃ NO.HCl: C, 71.79; H, 7.61; N, 4.41. Found:C, 71.63; H, 7.80; N, 4.21.

EXAMPLE 34 A. 2-(3-Phenoxyphenyl)propylamine

One hundred grams of 2-(3-phenoxyphenyl)propionitrile, preparedaccording to Example 2D, 10 g. of Raney nickel, 250 ml. of ethylalcohol, and 150 g. of ammonia were combined in a pressure vessel underan initial hydrogen pressure of 1000 p.s.i. The reaction was maintainedunder pressure, and heated at 70°-80°C., with shaking, for 4 hours,resulting in a 91 percent hydrogen uptake. After cooling and filteringthe catalyst, the reaction mixture was poured into ice water, acidifiedwith hydrochloric acid, washed with ethyl ether, basified with 10percent sodium hydroxide, and extracted with ethyl ether. The ethylether layer was washed with water, dried over sodium sulfate, andevaporated to a residual oil, which was distilled to yield 78.9 g. of2-(3-phenoxyphenyl)propylamine b.p., 158°-161°C./0.08 mm., n_(D) ²⁵ =1.5752.

Analysis, Calc. for C₁₅ H₁₇ NO: C, 79.26; H, 7.54; N, 6.16. Found: C,79.18; H, 7.29; N, 6.07.

B. 2-(3-Phenoxyphenyl)propylamine hydrochloride

Twenty grams of the above-prepared 2-(3-phenoxyphenyl)propylamine weredissolved in ethyl ether, and the resulting solution was saturated withhydrogen chloride gas, whereupon a solid precipitate formed. Theprecipitate was filtered, washed with ethyl ether, and dissolved in hotethyl alcohol. Ethyl ether was added to turbidity, and the reactionmixture was cooled and scratched to yield 18.9 g. of2-(3-phenoxyphenyl)propylamine hydrochloride, m.p., 147°-147.5°C.

Analysis, Calc. for C₁₅ H₁₇ NO.HCl: C, 68.30; H, 6.88; N, 5.31. Found:C, 68.11; H, 6.58; N, 5.32.

EXAMPLE 35 A. Ethyl 2-(3-phenoxyphenyl)propionate

Two hundred grams of 2-(3-phenoxyphenyl)propionic acid, preparedaccording to Example 2, were dissolved in 1500 ml. of ethanol, andhydrogen chloride gas was passed into the ethanolic solution until itwas saturated. The reaction mixture was then refluxed with stirringovernight after which a large portion of the ethanol was evaporated invacuo, and the remaining reaction mixture was poured into ice water. Thereaction mixture was basified with 10 percent sodium hydroxide, andextracted twice with ethyl ether. The combined ether extracts werewashed twice with water and dried over sodium sulfate. The ethyl etherwas evaporated, leaving crude ethyl 2-(3-phenoxyphenyl)propionate as anoily residue. The preparation was repeated with an additional 200 g. of2-(3-phenoxyphenyl)propionic acid. The crude residues were combined anddistilled through a 15 cm. Vigreux column to yield 339.9 g. of ethyl2-(3-phenoxyphenyl)propionate, b.p., 128°-134°C./0.15 mm., n_(D) ²⁵ =1.5458.

Analysis, Calc. for C₁₇ H₁₈ O₃ : C, 75.53; H, 6.71. Found: C, 75.75; H,6.70.

B. 2-(3-Phenoxyphenyl)propanol

To 27.4 g. of lithium aluminum hydride in a flame dried,nitrogen-flushed flask was added approximately 1 liter of ethyl ether.The mixture was stirred vigorously for 45 minutes. Three hundred gramsof ethyl 2-(3-phenoxyphenyl)propionate, prepared according to section Aabove, dissolved in 500 ml. of ethyl ether were then added dropwise tothe lithium aluminum hydride suspension at such a rate that a gentlereflux was constantly maintained. After the ester addition was complete,the reaction mixture was stirred and refluxed gently overnight. Aftercooling the reaction to room temperature, decomposition was achieved bythe cautious, dropwise addition of 44.5 ml. of water, 33.3 ml. of 20percent sodium hydroxide and 155 ml. of water. A large amount of waterwas then added which formed an emulsion. This became clear whenacidified. The reaction was then extracted with ethyl ether, the etherlayer separated, and the aqueous layer extracted again with ethyl ether.The ether extracts were combined, washed with water, dried over sodiumsulfate and a little sodium carbonate. The dried ether solution was thenevaporated to an oily residue. This was distilled to yield 241.6 g. of2-(3-phenoxyphenyl)propanol, b.p., 128°-131°C./0.1 mm., n_(D) ²⁵ =1.5771.

Analysis, Calc. for C₁₅ H₁₆ O₂ : C, 78.92; H, 7.06. Found: C, 78.65; H,7.17.

EXAMPLE 36 2-(3-Phenoxyphenyl)propyl-N-methylcarbamate

To a solution of 2.51 g. of methyl isocyanate in 75 ml. of dry benzenewas added dropwise with stirring at room temperature a solution of 10 g.of 2-(3-phenoxyphenyl)propanol, prepared according to Example 35, in 25ml. of benzene, and the resulting reaction mixture was refluxed withstirring for 5 hours. The reaction mixture was then evaporated to anoil, and the oil distilled to yield 8.7 g. of2-(3-phenoxyphenyl)propyl-N-methyl-carbamate, b.p., 170°-180°C./0.1 mm.,n_(D) ²⁵ = 1.5615.

Analysis, Calc. for C₁₇ H₁₉ NO₃ : C, 71.56; H, 6.71; N, 4.91. Found: C,71.64; H, 6.90; N, 4.77.

EXAMPLE 37 2-(3-Phenoxyphenyl)propyl Acetate

Eleven and four-tenths g. of 2-(3-phenoxyphenyl)propanol, preparedaccording to Example 35, 7 ml. of acetic anhydride, and approximately100 ml. of pyridine were combined, and refluxed, with stirring, for 18hours. Most of the pyridine was evaporated in vacuo, and the residue wasdissolved in chloroform, washed with dilute hydrochloric acid, water,and dried over anhydrous sodium sulfate. The chloroform was removed byevaporation in vacuo and the resulting oily residue was distilled,yielding 10.6 g. of 2-(3-phenoxyphenyl)propyl acetate, b.p.,138°-145°C./0.1 mm., n_(D) ²⁵ = 1.5478.

Analysis, Calc. for C₁₇ H₁₈ O₃ : C, 75.53; H, 6.71. Found: C, 75.40; H,6.59.

EXAMPLE 38 2-(3-Phenoxyphenyl)propyl propionate

2-(3-Phenoxyphenyl)propyl propionate was similarly prepared usingappropriate starting materials, b.p., 142°-149°C./0.1 mm., n_(D) ²⁵ =1.5420.

Analysis, Calc. for C₁₈ H₂₀ O₃ : C, 76.03; H, 7.09. Found: C, 75.73; H,7.32.

EXAMPLE 39 2-(3-Phenoxyphenyl)propionohydroxamic acid

Sodium methoxide was prepared by the addition of 5 g. of sodium metal to150 ml. of methanol. A solution of 7 g. of hydroxylamine hydrochloridedissolved in 100 ml. of methanol was then added to the cooled sodiummethoxide solution, and the precipitated sodium chloride removed byfiltration. Twenty-five and six-tenths grams of methyl2-(3-phenoxyphenyl)propionate, prepared according to the method ofExample 35, except that methanol was used in place of ethanol, were thenadded to the filtrate with stirring. The reaction mixture was stirred atroom temperature for one-half hour and then refluxed, with stirring, forone and one-half hours. The reaction mixture was then cooled andacidified by the dropwise addition of 6N hydrochloric acid. Afterpartial solvent removal in vacuo, a yellow oil formed, whichsubsequently crystallized. Recrystallization from a small amount ofethyl acetate and methylcyclohexane yielded 12.2 g. of2-(3-phenoxyphenyl)propionohydroxamic acid, m.p., 121°-122°C.

Analysis, Calc. for C₁₅ H₁₅ NO₃ : C, 70.02; H, 5.88; N, 5.44. Found: C,69.95; H, 5.96; N, 5.41.

EXAMPLE 40

Various compounds within the scope of this invention were tested foranti-inflammatory activity in an erythema blocking assay which involvedthe following test procedure.

A modification of the Winder et al. (1958) method [Winder, C. V., Wax,J., Burr, V. and Posiere, C. E.: "A Study of Pharmacological Influenceson Ultraviolet Erythema in Guinea Pigs", Arch. Int. Pharmacodyn., 116,261, 1958] was used to measure anti-inflammatory activity of thesecompounds. Albino guinea pigs of either sex weighing 225-300 grams wereshaved on the back and chemically (NAIR, Lotion Hair Remover, CarterProducts, N. Y., N. Y.) depitated 18-20 hours before exposure toultraviolet light. The animals were fasted overnight. Immediately afterthe guinea pigs were treated with a test compound, gummed notebook paperreinforcements were placed on their backs, and they were exposed to ahigh intensity ultraviolet light for 7 seconds. The ultraviolet lightsource was a Hanovia Lamp (Kromayer-Model 10) which was placed incontact with the skin of the guinea pig's back. After exposure, thereinforcements were removed and their backs wiped clean with a watersoaked gauze sponge. The unexposed area under the reinforcementsprovided an area of contrast for grading the erythema. The animals wererandomized and placed in clear plastic partitioned holders 10 × 20 cm.wide and 15 cm. high. Beginning 1 hour after exposure and thereafter athalf-hour intervals for another 11/2 hours, the degree of resultingerythema was graded by an arbitrary scoring system based upon the degreeof contrast and redness formed. Anti-inflammatory agents delay thedevelopment of the erythema and therefore have their greatest effect atthe initial grading periods. Therefore, the scores were weighed by afactor of 4, 3, 2, and 1 at the 1.0-, 1.5-, 2.0-, and 2.5-hour scoringtimes, respectively. The erythema was graded as follows:

    Erythema Scoring System                                                       Score Appearance of Exposed Area                                              ______________________________________                                        0     No redness and no contrast                                              1     Slight redness with a faint reinforcement outline                       2     Slight to moderate redness with a distinct outline                      3     Marked redness with a distinct circular outline                         ______________________________________                                    

Total scores from each treatment group of five or six guinea pigs werecompared to the control treatment and the percent inhibition calculatedas follows: ##EQU1##

Test compounds were prepared in a suspension of 1 percentmethylcellulose in water and administered orally. Guinea pigs weretreated orally with 1.0 cc./kg. of the suspensions. Control animalsreceived 1.0 cc./kg. of a 1 percent methylcellulose suspension. The dosethat produces a 50 percent inhibition of the erythemic response (ED₅₀)was calculated. The ED₅₀ results in (mg./kg.) are recorded in thefollowing table:

    ______________________________________                                         ##STR14##                                                                                       Erythema Blocking Assay                                                       Oral ED.sub.50 (mg. of com-                                R                  pound/kg. of body wt.)                                     ______________________________________                                        CH.sub.2 CH.sub.2 NH.sub.2.HCl                                                                   75                                                         CH.sub.2 CH.sub.2 NHCH.sub.3.HCl                                                                 10                                                         CH.sub.2 CH.sub.2 N(CH.sub.3).sub.2.HCl                                                          7                                                           ##STR15##         1                                                           ##STR16##         1                                                           ##STR17##         8                                                           ##STR18##         9                                                           ##STR19##         20                                                          ##STR20##         3                                                           ##STR21##         3                                                           ##STR22##         10                                                          ##STR23##         3                                                           ##STR24##         5                                                           ##STR25##         15                                                          ##STR26##         5                                                           ##STR27##         2                                                           ##STR28##         5                                                           ##STR29##         2                                                           ##STR30##         8                                                           ##STR31##         10                                                          ##STR32##         40                                                          ##STR33##         3                                                           ##STR34##         10                                                          ##STR35##         30                                                          ##STR36##         25                                                          ##STR37##         2                                                           ##STR38##         5                                                          A.S.A.             50                                                         ______________________________________                                    

EXAMPLE 41

The inhibition of acetic acid-induced writhing in mice is used herein todemonstrate the relative analgesic activity of various compounds withinthe scope of this invention. A method similar to that reported byKoster, R., et al., "Acetic Acid for Analgesic Screening" Fed. Proc.,18:412(1959) was used to demonstrate the analgesic effects.

METHOD

Standard strain albino male mice, weighing 16-18 grams, wereadministered the treatments either subcutaneously or by gastric lavage.At various times after treatment, writhing was induced by theintraperitoneal administration of 60 mg./kg. of acetic acid (0.6 percent). Each treatment group consisted of 6 mice. The total number ofwrithes for the treatment group were counted in a 10-minute observationperiod starting 5 minutes after the acetic acid administration. Thetreatment totals were compared to controls and a percent inhibitioncalculated as follows: ##EQU2##

The ED₅₀ values in the table which follows represents the doses in mg.of compound/kg. of body weight which will produce a 50 percentinhibition of the frequency of writhing.

    ______________________________________                                        Test Compounds       Analgesic Writhing Test                                  2-(3-phenoxyphenyl)-R                                                                              Subcutaneous ED.sub.50                                   where R is           mg./kg.                                                  ______________________________________                                        CH.sub.2 CH.sub.2 NH.sub.2.HCl                                                                     4                                                        CH.sub.2 CH.sub.2 NHCH.sub.3.HCl                                                                   25                                                        ##STR39##           35                                                        ##STR40##           20                                                        ##STR41##           20                                                        ##STR42##           10                                                        ##STR43##           20                                                        ##STR44##           <50                                                      A.S.A., (Aspirin, Lilly)                                                                           20                                                       ______________________________________                                    

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, at least one of thecompounds of this invention in association with a pharmaceutical carrieror diluent. The compounds of this invention exhibit both oral andparenteral activity and can be formulated in dosage forms for oral,parenteral, rectal, or topical administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert diluent such as sucrose,lactose, or starch. Such dosage forms can also comprise, as is normalpractice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water.Besides inert diluents, such compositions can also include adjuvants,such as wetting agents, emulsifying and suspending agents, andsweetening, flavoring, and perfuming agents.

Preparations according to this invention for parenteral administrationinclude sterile aqueous or non-aqueous solutions, suspensions, oremulsions. Examples of non-aqueous solvents or vehicles are propyleneglycol, polyethylene glycol, vegetable oils, such as olive oil, andinjectable organic esters such as ethyl oleate. Such dosage forms mayalso contain adjuvants such as preserving, wetting, emulsifying, anddispersing agents. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, by incorporating sterilizing agentsinto the compositions, by irradiating the compositions, or by heatingthe compositions. They can also be manufactured in the form of sterilesolid compositions which can be dissolved in sterile water, or someother sterile injectable medium immediately before use.

Compositions for rectal administration are suppositories which maycontain in addition to the active substance, excipients such as cacoabutter or a suppository wax.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient shall be such that a suitable dosage form is obtained. Theselected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment.Generally, dosage levels of between 0.5 to 50 mg./kg. of body weightdaily are administered to mammals to obtain effective relief ofinflammation, pain, and fever.

The following examples further illustrate the pharmaceuticalcompositions which are a feature of this invention.

EXAMPLE 42

Tablets weighing 500 mg. and having the following compositions areprepared:

    2-(3-phenoxyphenyl)propylamine hydrochloride                                                            250 mg.                                             starch                    190 mg.                                             colloidal silica          50 mg.                                              magnesium stearate        10 mg.                                          

EXAMPLE 43

Tablets weighing 200 mg. and having the following compositions areprepared:

    N-Methyl-2-(3-phenoxyphenyl)propylamine                                        hydrochloride          50 mg.                                                starch                  120 mg.                                               colloidal silica        27 mg.                                                magnesium stearate      3 mg.                                             

Tablets analogous to those described in Examples 49 and 50 can beprepared by replacing the above active ingredients by the same weight ofany other compound coming within the scope of this invention. Suchtablets can be enteric coated and can additionally comprise bufferingagents and the like.

EXAMPLE 44

2-(3-phenoxyphenyl)propanol can be encapsulated in a soft gelatin filmeither neat or mixed with a suitable liquid diluent such as a vegetableoil. Other ingredients can be added if required for purposes such asimproving dispersibility, promoting absorption, etc. Encapsulation canbe accomplished by any suitable machine such as the Scherer rotary diemachine described in "Remington's Pharmaceutical Sciences", 13th Ed.,and well known in the art.

EXAMPLE 45

    Suppository Formulation                                                       ______________________________________                                        2-(3-phenoxyphenyl)propylamine hydro-                                          chloride               15.5% by wt.                                          White Wax, U.S.P.        4.0%                                                 Theobroma Oil, U.S.P.   80.5%                                                 ______________________________________                                    

White wax and the 2-(3-phenoxyphenyl)propylamine hydrochloride are mixedwith aid of gentle heat. Theobroma oil is shaved and added to themixture slowly. After the theobroma oil has been completely melted, withthe aid of additional heat as required, the mixture may be poured intosuppository molds of suitable size for the desired dose; e.g., a 2.28 g.suppository of the above mixture yields a 400 mg. dose of2-(3-phenoxyphenyl)propylamine hydrochloride.

EXAMPLE 46

    Emulsion Formulation                                                          ______________________________________                                        2-(3-phenoxyphenyl)lpropionyl N-methyl                                         carbamate               1.33    g.                                           Soybean Oil              26.7    g.                                           Span 60                  2.27    g.                                           Tween 60                 0.40    g.                                           Sucrose                  33.3    g.                                           Methylparaben            0.1     g.                                           Propylparaben            0.1     g.                                           Peppermint Oil           0.05    g.                                           Water q.s.               100.    ml.                                          Dose: 15 ml., equivalent to 200 mg. of drug.                                  ______________________________________                                    

The Span 60 and soybean oil are mixed and heated to 70°C. Tween 60 andparabens are dispersed in approximately 100 ml. of water at 70°C. andsucrose is added. The oil phase is added to the aqueous phase in asuitable mixer such as a Waring Blender and mixed to produce a milkyproduct. After cooling, the 2-(3-phenoxyphenyl)propionylN-methylcarbamate and peppermint oil are added, and the mixture isagitated again.

Span 60 is sorbitan monostearate -- Atlas Chemical Industries, Inc.

Tween 60 is polyoxyalkylene derivative of sorbitan monostearate -- CityChemical Corp., N.Y., N.Y.

I claim:
 1. A compound of the formula ##SPC3##wherein R₁ is hydrogen, C₁to C₅ -alkyl, C₂ to C₅ -alkenyl, C₂ -C₅ -alkynyl; n is an integer offrom 1 to 3; and each R₅ is the same or different and is hydrogen, C₁ toC₅ -alkyl, C₂ to C₆ -alkenyl, cyclopropyl, or cyclopropylmethyl, allyl,3-methyl-2-butenyl, or phenethyl; and the pharmaceutically acceptableacid addition salts thereof.
 2. A compound as defined in claim 1 whereinR₁ is C₁ to C₅ -alkyl, n is 1, and ##STR45##each R₅ is hydrogen, and thepharmaceutically acceptable acid addition salts thereof.
 3. A compoundas defined in claim 2 wherein the compound is2-(3-phenoxyphenyl)propylamine hydrochloride.
 4. A compound as definedin claim 1 wherein R₁ is C₁ to C₅ -alkyl, n is 1 and ##STR46##one R₅ ishydrogen and the other R₅ is C₁ to C₅ -alkyl, and the pharmaceuticallyacceptable acid addition salts thereof.
 5. A compound as defined inclaim 4 wherein the compound is 2-(3-phenoxyphenyl)-N-methylpropyl aminehydrochloride.
 6. A compound as defined in claim 1 wherein R₁ ishydrogen, n is 1, and ##STR47##each R₅ is hydrogen, and thepharmaceutically acceptable acid addition salts thereof.
 7. A compoundas defined in claim 6 wherein the compound is2-(3-phenoxyphenyl)ethylamine hydrochloride.
 8. A compound as defined inclaim 1 wherein R₁ is C₁ to C₅ -alkyl, n is 1, and ##STR48##one R₅ is C₁to C₅ -alkyl and the other R₅ is C₃ to C₆ -cycloalkyl, and thepharmaceutically acceptable acid addition salts thereof.
 9. A compoundas defined in claim 8 wherein the compound is2-(3-phenoxyphenyl)-N-methyl-N-cyclopropyl-propylamine hydrochloride.10. A compound as defined in claim 1 where R₁ is C₁ to C₅ -alkyl, n is2, and ##STR49##each R₅ is hydrogen, and the pharmaceutically acceptableacid addition salts thereof.
 11. A compound as defined in claim 10wherein the compound is 3-(3-phenoxyphenyl)butylamine hydrochloride. 12.A compound as defined in claim 1 wherein R₁ is C₁ to C₅ -alkyl, n is 1,and ##STR50##one R₅ is C₁ to C₅ -alkyl and the other R₅ is C₂ to C₆-alkenyl, and the pharmaceutically acceptable salts thereof.
 13. Acompound as defined in claim 12 wherein the compound is2-(3-phenoxyphenyl)-N-allyl-N-methyl-propylamine hydrochloride.
 14. Acompound as defined in claim 12 wherein the compound is2-(3-phenoxyphenyl)-N-methyl-N-(3-methyl-2-butenyl)propylaminehydrochloride.
 15. A compound as defined in claim 1 wherein R₁ is C₁ toC₅ -alkyl, n is 1, and ##STR51##one R₅ is hydrogen and the other R₅ isC₃ to C₆ -cycloalkyl, and pharmaceutically acceptable salts thereof. 16.A compound as defined in claim 15 wherein the compound is2-(3-phenoxyphenyl)-N-cyclopropyl-propylamine hydrochloride.